US8907117B2 - Anti-tumor and anti-inflammatory dicinnamoyl-glycerol esters and their analogues - Google Patents
Anti-tumor and anti-inflammatory dicinnamoyl-glycerol esters and their analogues Download PDFInfo
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- US8907117B2 US8907117B2 US13/608,599 US201213608599A US8907117B2 US 8907117 B2 US8907117 B2 US 8907117B2 US 201213608599 A US201213608599 A US 201213608599A US 8907117 B2 US8907117 B2 US 8907117B2
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- dimethoxyphenyl
- ylide
- tumor
- dicinnamate
- inflammatory
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
- C07C67/26—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran with an oxirane ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
Definitions
- the present invention relates to anti-cancer drug and, more particularly, to synthetic dicinnamate compounds and their analogues that exhibit anti-tumor activity and/or an anti-inflammatory activity, that has beneficial activity principally in destroying cancer cells.
- drugs include alkylating agents, intercalating agents, antimetabolites, etc., most of which target DNA or enzymes regulating the DNA duplication and elongation process.
- alkylating agents include alkylating agents, intercalating agents, antimetabolites, etc., most of which target DNA or enzymes regulating the DNA duplication and elongation process.
- rapidly growing tumors do not always exhibit high levels of cell proliferation, but may also exhibit low levels of cell death compared to the normal cell population from which these tumor cells issue, For these types of rapidly growing tumors, the mentioned drugs are not effective.
- the great majority of the drugs currently available for treatment of cancer are toxic and involve detrimental side-effects on healthy cells, tissues and organs.
- a successful anticancer drug should kill or incapacitate cancer cells without causing excessive damage to normal cells. This ideal situation is achievable by inducing apoptosis in cancer cells without undue side effects, and organic drugs are well-suited.
- Apoptosis is a programmed cell death initiated by the nucleus. Apoptosis is a mechanism of cell death that incurs little or no inflammatory response.
- radiation is effective in producing cell death by apoptosis but is dependent on dose rate as well as ionization density, and this subjects other non-tumor cells to radiation risks.
- Natural products are the most consistently successful source of drug leads. However, natural products inherently depend on availability of scarce resources. Indeed, certain natural drugs are derived from rare and/or exotic plants and this can severely curtail the supply. It is very common, therefore, for scientists to attempt to isolate and synthesize the active component(s) of such rare natural drugs.
- the present inventor disclosed methods of treating cancer by administering a composition comprising and extract of Jamaican Ball Moss ( Tillandsia recurvata ) in a therapeutic compound. Jamaican Ball Moss is not found in abundance, and not at all outside Jamaica, and as described herein the present inventor has devoted significant subsequent effort to isolating the active compound and synthesizing it.
- the primary object of the present invention to provide a synthetic therapeutic drug based on natural extracts that kills cancerous tumor cells by apoptosis.
- the present invention is a synthetic therapeutic drug chosen from among the group comprising:
- the present invention also includes the method of synthesizing the foregoing.
- the synthase may be used as an anti-cancer drug with possibly other therapeutic uses (i.e. anti-inflammatory), and a high-level of efficacy has been shown by positive test results.
- FIG. 1 shows the chemical structure of the synthesized dimethoxy-dicinnamate analog of the present invention:
- FIG. 2 shows the chemical structure of the synthesized dihydroxy-dicinnamate analog of the present invention
- FIG. 3 shows the chemical structure of the synthesized di-acetoxy/benzoic acid analog of the present invention
- FIG. 4 shows the synthetic reaction scheme for the analog of FIG. 1 ;
- FIG. 5 shows the synthetic reaction scheme for the analog of FIG. 2 ;
- FIG. 6 shows an alternative synthetic reaction scheme for the analog of FIG. 2 ;
- FIG. 7 shows the synthetic reaction scheme for the analog of FIG. 3 ;
- FIG. 8 illustrates the acetylation reaction for the analog of FIG. 3 .
- the present invention is a group of synthetic dicinnamate compounds and their analogues that exhibit anti-tumor activity and/or an anti-inflammatory activity, that have beneficial activity principally in destroying cancer cells.
- the dicinnamate compounds are synthetic version of an isolated extract of plant biomass. Specifically, in his U.S. Pat. No. 7,713,556 issued May 11, 2010 the present inventor established an anti-tumor activity and/or an anti-inflammatory activity in the indigenous Jamaican plant Ball Moss ( Tillandsia recurvata ).
- the dicinnamate molecule and its analogs were synthesized, their chemical nature was determined, and their anti-cancer bio-activity was established by potent in vitro and in vivo anticancer test results on several different refractory cancer cell lines.
- Tillandsia recurvate (Jamaican Ball Moss) was subjected to conventional drying techniques such as convective drying, sun drying, room air drying and solar drying (using polythene tent dryer), and the dried specimen was milled.
- the milled specimen was mixed with either a halogenated hydrocarbon solvent such as chloroform, or an alcohol solvent such as methanol, and the methanol extract and chloroform extracts were filtered and subjected to NMR spectroscopic analysis.
- dicinnamate molecule specifically 1,3-di-O-cinnamoyl glycerol, (E)-3-(cinnamoyloxy)-2-hydroxypropyl 3-(3,4-dimethoxyphenyl)acrylate), and ethyl caffeiate were detected in both methanol and chloroform extracts.
- the dicinnamate molecule and its analogs were synthesized, their chemical nature was determined, and their anti-cancer bio-activity was established.
- FIGS. 1-3 The synthesis of three dicinnamate compounds, FIGS. 1-3 was completed successfully as described below.
- the three synthetic dicinnamate compound analogs are shown in FIGS. 1-3 and include:
- the first step involves taking phosphonium bromide and chemically producing the triphenyl phosphonium ylide.
- the second step relies on a Wittig reaction, a lesser-known reaction used in organic synthesis for the preparation of alkenes.
- a Wittig reagent (aldehyde) is reacted with the triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide.
- the third step is joining the two key components together. Specifically, the steps are:
- the reaction scheme for the analog of FIG. 1 is shown graphically in FIG. 4 , with the end result of (E)-2-hydroxy-3-((E)-3-p-tolylacryloyloxy)propyl 3-(3,4-dimethoxyphenyl)acrylate.
- the mass spectrometer was operated in positive ion mode.
- the analog of FIG. 2 may be synthesized from suitably protected caffeic acid. This synthesis strategy is shown in FIG. 5 . Caffeic acid is treated with acetic anhydride to give 2,3-diacetyl caffeic acid. The glycerol backbone is then formed by way of oxiran-2-ylmethyl cinnamate. In practice several attempts were made varying the molar ratio of 2,3-diacetylcaffeic acid to oxiran-2-ylmethyl cinnamate within a range of from 2.5:1 to 1.5:1 to 1:1. In all instances, desired product was detected using LC/MS. Identity was based on an ion of 407 which is consistent for loss of a proton under negative ionization electrospray conditions employed in the mass spectrometer. An alternative approach to the analog of FIG. 2 may use the reaction scheme of FIG. 6 .
- This compound called for acetylation of 4-Formyl-2-Hydroxybenzoic Acid under standard conditions, as illustrated in FIG. 8 .
- a coupling with 2-formyl-5-hydroxybenzoic acid was also attempted.
- running the reaction with acetic anhydride (AC 2 O) and triethylamine (TEA) at reflux successfully drove the reaction to completion.
- Reaction between the 2-acetoxy-5-formylbenzoic acid and a 5-formyl-2-hydroxybenzoic acid ylide went smoothly to yield FIG. 3 .
- FIGS. 1-3 The biomass equivalents of FIGS. 1-3 were tested in vitro against the potent melanoma B-16 cell lines utilizing the extremely sensitive 3H thymidine incorporation in vitro. The results are encouraging, with similar efficacy as a number of clinically proven anticancer agents including Paclitaxel (Taxol®), isolated from the bark of the Pacific Yew tree.
- Paclitaxel Texol®
- ADME/TOX absorption, distribution, metabolism, elimination and toxicity
- cancer cell line selectivity in vitro studies in vivo animal efficacy and toxicity studies
- in vivo pharmacokinetic studies both in vitro and in vivo mechanism of action (MOA) studies
- MOA mechanism of action
- SAR structure-activity relationship
- medicinal chemistry studies all of which should further improve efficacy and reduce toxicity of the synthetic compounds to improve the therapeutic index.
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
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US201161532267P | 2011-09-08 | 2011-09-08 | |
US13/608,599 US8907117B2 (en) | 2011-09-08 | 2012-09-10 | Anti-tumor and anti-inflammatory dicinnamoyl-glycerol esters and their analogues |
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DK2486026T3 (en) * | 2009-10-09 | 2020-08-17 | Alexander Macgregor | DERIVATIVES OF DI (PHENYLPROPANOID) GLYCEROL FOR CANCER TREATMENT |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US20090136566A1 (en) * | 2006-04-13 | 2009-05-28 | Regents Of The University Of Minnesota | Therapeutic triterpenoids |
US7713556B2 (en) | 2006-12-08 | 2010-05-11 | Henry Lowe | Anti-tumor and anti-inflammatory extracts of plant biomass and their uses |
CA2715662A1 (en) * | 2009-10-09 | 2010-12-14 | Alexander Macgregor | Phenylpropanoid diglycerides for the treatment of cancer |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20090136566A1 (en) * | 2006-04-13 | 2009-05-28 | Regents Of The University Of Minnesota | Therapeutic triterpenoids |
US7713556B2 (en) | 2006-12-08 | 2010-05-11 | Henry Lowe | Anti-tumor and anti-inflammatory extracts of plant biomass and their uses |
CA2715662A1 (en) * | 2009-10-09 | 2010-12-14 | Alexander Macgregor | Phenylpropanoid diglycerides for the treatment of cancer |
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